The 5-HT6 receptor is a member of the G-protein coupled receptor superfamily of serotonin receptors, and, like the 5-HT4 and 5-HTS receptors, is positively coupled to adenylate cyclase (Monsma, F. et al. Mol. Pharmacol. 1993, 43, 3, 320-327). The rat 5-HT6 receptor was first cloned in 1993 and the cloning of the human homologue, to which it shares an 89% sequence identity, was reported in 1996 (Kohen, R. et al. J Neurochem. 1996, 66, 1, 47-56). The localization of 5-HT6 receptors in rat brain has been studied using mRNA quantification by Northern analysis and RT-PCR, immunohistochemistry, and autoradiography (Ward, R., et al. J. Comp Neurol. 1996, 370, 3, 405-414; and Ward, R. et al. Neuroscience 1995, 64, 4, 1105-1111). These methods have consistently found high levels of the receptor in olfactory tubercle, hippocampus, striatum, nucleus accumbens, and cortical regions. 5-HT6 receptors are either absent or present in very low levels in peripheral tissues.
Much of the early interest in the 5-HT6 receptor was due to the observation that several psychotropic agents are high affinity antagonists at the human 5-HT6, receptor. These compounds include amitriptyline (Ki=65 nM) and the atypical antipsychotics clozapine (Ki=9.5 nM), olanzapine (Ki=10 nM), and quetiapine (33 nM). See Roth, B. L., et al. J. Pharmacol. Exp. Ther. 1994, 268, 3, 1403-1410.
The use of selective 5-HT6 receptor antagonists to treat cognitive dysfunction is widely accepted and is based on several lines of reasoning. For example, selective 5-HT6 receptor antagonists modulate cholinergic and glutamatergic neuronal function. Cholinergic and glutamatergic neuronal systems play important roles in cognitive function. Cholinergic neuronal pathways are known to be important to memory formation and consolidation. Centrally acting anticholinergic agents impair cognitive function in animal and clinical studies and loss of cholinergic neurons is one of the hallmarks of Alzheimer's disease. Conversely, stimulation of cholinergic function has been known to improve cognitive performance and two agents currently approved for the treatment of cognitive deficit in Alzheimer's disease, galantamine and donepezil, are both acetylcholinesterase inhibitors. The glutamatergic system in the prefrontal cortex is also known to be involved in cognitive function (Dudkin, K. N., et al. Neurosci. Behav. Physiol. 1996, 26, 6, 545-551).
The activity of selective 5-HT6 receptor antagonists is also demonstrated in animal models of cognitive function. Since the disclosure of the first selective 5-HT6 receptor antagonists, there have been several reports on the activity of these selective compounds in models of cognitive function. For example, the selective 5-HT6 receptor antagonist SB-271046 improved performance in the Morris water maze (Rogers, D. et al. Br. J. Pharamcol. 1999, 127 (suppl.): 22P). These results were consistent with the finding that chronic i.c.v. administration of anti-sense oligonucleotides directed toward the 5-HT6 receptor sequence led to improvements in some measures of performance in the Morris water maze (Bentley, J. et al. Br. J. Pharmacol. 1999, 126, 7, 1537-42). SB-271046 treatment also led to improvements in the spatial alternation operant behavior test in aged rats.
Currently, several 5-HT6 receptor antagonists are in clinical development as potential treatments for cognitive dysfunction disorders. A first report that a 5-HT6 receptor antagonist, SB-742457, is of clinical benefit in Alzheimer's patients provides further evidence of the therapeutic potential of this approach.
N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine is a potent and selective 5-HT6 receptor antagonist which is currently in clinical development. Its chemical structure is depicted below as the compound of Formula I.

The synthesis of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, its use for the treatment of disorders such as cognitive dysfunction disorders, and pharmaceutical compositions comprising this substance are disclosed in U.S. Pat. No. 7,157,488 (“the '488 patent”). The '488 patent further describes the preparation of the corresponding monohydrochloride salt.
Although the synthetic methods disclosed in the above-identified reference suffices to prepare small quantities of material, it suffers from a variety of safety issues, low yields or processes that are not amendable to large scale synthesis. Thus, an unmet need exists to identify processes for the manufacture of the compound of Formula I.
Accordingly, the present invention describes an efficient and economical process for the preparation of the compound of Formula I that is useful for the production of kilogram quantities of material for preclinical, clinical and commercial use. In particular, the inventors have unexpectedly discovered the role of ammonia to prevent dimerization in connection with the reduction of the nitrile containing intermediate to the corresponding amine.